Development of PET probes of neuroprotective molecular components in oriental medicines

• Project/Area Number: 25242070
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biomolecular chemistry
• Research Institution: National Center for Geriatrics and Gerontology
• Principal Investigator: SUZUKI Masaaki 国立研究開発法人国立長寿医療研究センター, 能機能画像診断開発部, 特任研究員 (90093046)
• Co-Investigator(Kenkyū-buntansha): ISHII Hideki 独立行政法人放射線医学総合研究所, 分子イメージング研究センター, 主任研究員 (80425610) ; DOI Hisashi 独立行政法人理化学研究所, ライフサイエンス技術基盤研究センター, チームリーダー (00421818) ; KOYAMA Hiroko 岐阜大学, 大学院医学系研究科, 助教 (50402160)
• Co-Investigator(Renkei-kenkyūsha): UMEMURA Kazuo 浜松医科大学, 医学部, 教授 (40232912)
• Research Collaborator: OGATA Aya
• Project Period (FY): 2013-10-21 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥43,940,000 (Direct Cost: ¥33,800,000、Indirect Cost: ¥10,140,000); Fiscal Year 2015: ¥15,210,000 (Direct Cost: ¥11,700,000、Indirect Cost: ¥3,510,000); Fiscal Year 2014: ¥15,080,000 (Direct Cost: ¥11,600,000、Indirect Cost: ¥3,480,000); Fiscal Year 2013: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
• Keywords: 11C標識 / PET分子イメージング / ギンゴライド＆ジンセノサイド / 脳移行性 / 糖輸送体 / PETプローブ / 11C,18F-標識化 / 認知症改善薬ギンゴライド＆ギンセノシド / グルコーストランスポーター / 高速メチル化 / クロスメタセシス / PET分子プローブ / 分子イメージング / グルコース / 高速クロスカップリング / クロスメタセシス反応 / 認知症(脳機能)改善漢方薬成分 / ギンゴライド / ギンセノシド / 高速クロスカップリング反応

Outline of Final Research Achievements

The ginkgolide is the most attractive components of the ginkgo biloba extracts, possessing neuroprotective effects. It has been reported that ginkgolide B (GB) shows almost no brain permeability as judged by PET molecular imaging. Here, we have found that the GB benzyl derivative with enhanced hydrophobicity shows higher binding affinity for PAF receptor than GB and that the corresponding 11C-labeled methylbenzyl GB exhibits monkey-brain permeability to some extent and high brain uptake for the rat after pre-administration of P-glycoprotein inhibitor. Moreover, in expectation of further higher uptake of GB into the brain, we have synthesized a new prodrug linked with glucose as a substrate for a glucose transporter expressed in the blood-brain barrier. In addition, we have established the synthesis of boron and stannyl precursors of dipterocarpol submitted for our-devised rapid C-[11C]methylation, eventually with an aim to synthesize a 11C-labeled ginsenoside.

Research Products

• [Journal Article] Detection of Cyclooxygenase-1 in Activated Microglia During Amyloid Plaque Progression: PET Studies in Alzheimer's Disease Model Mice. (2016)
  • Author(s): Miho Shukuri, Aya Mawatari, Masahiro Ohno, Masaaki Suzuki, Hisashi Doi, Yasuyoshi Watanabe, Hirotaka Onoe
  • Journal Title: Journal of Nuclear Medicine Volume: 57 Issue: 2 Pages: 291-296
  • DOI: 10.2967/jnumed.115.166116
  • Peer Reviewed / Open Access
• [Journal Article] Synthesis of a Vpr-binding derivative for use as a novel HIV-1 inhibitor (2015)
  • Author(s): Kyoji Hagiwara, Hideki Ishii, Tomoyuki Murakami, Shin-nosuke Takashima, Nopporn Chutiwitoonchai, Eiichi N Kadama, Kumi Kawai, Yasumitsu Kondoh, Kaori Honda, Hiroyuki Osada, Yasuo Tsunetsugu-Yokota, Masaaki Suzuki, Yoko Aida
  • Journal Title: PLoS One Volume: 12
  • Peer Reviewed / Open Access
• [Journal Article] Toxic tau oligomer formation blocked by capping of cysteine residues with 1,2-dihydroxybenzene groups. (2015)
  • Author(s): Soeda Y, Yoshikawa M, Almeida OF, Sumioka A, Maeda S, Osada H, Kondoh Y, Saito A, Miyasaka T, Kimura T, Suzuki M, Koyama H, Yoshiike Y, Sugimoto H, Ihara Y, Takashima A
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 10216-10216
  • DOI: 10.1038/ncomms10216
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Synthesis of 11C-labeled thiamine and fursulthiamine for in vivo molecular imaging of vitamin B1 and its prodrug using positron emission tomography (2015)
  • Author(s): Hisashi Doi, Aya Mawatari, Masakatsu Kanazawa, Satoshi Nozaki, Yukihiro Nomura, Takahito Kitayoshi, Kouji Akimoto, Masaaki Suzuki, Shinji Ninomiya, Yasuyoshi Watanabe
  • Journal Title: J. Org. Chem. Volume: 80 Issue: 12 Pages: 6250-6258
  • DOI: 10.1021/acs.joc.5b00685
  • Peer Reviewed
• [Journal Article] A novel [11C]-labeled thymidine analog, [11C]AZT, for tumor imaging by positron emission tomography (2015)
  • Author(s): Tsuyoshi Tahara, Zhouen Zhang, Masahiro Ohno, Yukako Hirano, Nami Hasaka, Hisashi Doi, Masaaki Suzuki, and Hirotaka onoe
  • Journal Title: EJNMMI Res. Volume: 5 Issue: 1 Pages: 45-45
  • DOI: 10.1186/s13550-015-0124-0
  • Peer Reviewed / Open Access
• [Journal Article] Synthesis of 11C-labeled capsaicin and its application for in vivo molecular imaging in rats by positron emission tomography. (2015)
  • Author(s): Goto Miki, Mizuma Hiroshi, Wada Yasuhiro, Suzuki Masaaki, Watanabe Yasuhiro, Onoe Hirotaka, Doi Hisashi
  • Journal Title: Food and Nutrition Science Volume: 6 Issue: 02 Pages: 216-220
  • DOI: 10.4236/fns.2015.62022
  • Peer Reviewed / Open Access
• [Journal Article] IOP lowering effect of isoquinoline-5-sulfonamide compounds on ocular normotensive monkey. (2014)
  • Author(s): Kengo Sumi, Yoshihiro Inoue, Masahiro Nishio, Yasuhito Naito, Takamitu Hosoya, Masaaki Suzuki, Hiroyoshi Hidaka
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 24 Issue: 3 Pages: 831-834
  • DOI: 10.1016/j.bmcl.2013.12.085
  • Peer Reviewed
• [Journal Article] [11C]Cetrozole: an improved C-[11C]methylated PET probe for aromatase imaging in the brain. (2014)
  • Author(s): Kayo Takahashi, Takamitsu Hosoya, Kayo Onoe, Hisashi, Doi, Hiroko Nagata, Toshiyuki Hiramatsu, Xiao-Le Li, Yumiko Watanabe, Yasuhiro Wada, Tadayuki Takashima, Masaaki Suzuki, Hirotaka Onoe, Yasuyoshi, Watanabe
  • Journal Title: J. Nucl. Med. Volume: 55 Issue: 5 Pages: 852-857
  • DOI: 10.2967/jnumed.113.131474
  • Peer Reviewed
• [Journal Article] Quantitative Evaluation of the Improvement in the Pharmacokinetics of a Nucleic Acid Drug Delivery System by Dynamic PET Imaging with 18F-incorporated Oligodeoxynucleotides (2014)
  • Author(s): H. Mukai, D. Ozaki, Y. Cui, T. Kuboyama, H. Yamato-Nagata, K. Onoe, M. Takahashi, Y. Wada, T. Imanishi, T. Kodama, S. Obika,* M Suzuki, H. Doi, Y. Watanabe
  • Journal Title: J. Controlled Release Volume: 180 Pages: 92-99
  • DOI: 10.1016/j.jconrel.2014.02.014
  • Peer Reviewed
• [Journal Article] Pd(0)-mediated rapid cross-coupling reactions, the rapid C-[11C]methylations, revolutionally advancing the syntheses of short-lived PET molecular probes (2014)
  • Author(s): Masaaki Suzuki, Hisashi Doi, Hiroko Koyama, Zhang Zhouen, Takamitsu Hosoya, Hirotaka Onoe, Yasuyoshi Watanabe
  • Journal Title: Chem. Rec. Volume: 14 Issue: 3 Pages: 516-541
  • DOI: 10.1002/tcr.201400002
  • Peer Reviewed
• [Journal Article] Synthesis of 11C-labeled retinoic acid, [11C]ATRA, via an alkenylboron precursor by Pd(0)-mediated rapid C-[11C]methylation (2014)
  • Author(s): Masaaki Suzuki, Misato Takashima-Hirano, Hideki Ishii, Chika Watanabe, Kengo Sumi, Hiroko Koyama, Hisashi Doi,
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 24 Issue: 15 Pages: 3622-3625
  • DOI: 10.1016/j.bmcl.2014.05.041
  • Peer Reviewed
• [Journal Article] Efficient syntheses of [11C]zidovudine and its analogues by convenient one-pot palladium(0)-copper(I)co-mediated rapid C-[11C]methylation. (2014)
  • Author(s): Zhouen Zhang, Hisashi Doi, Hiroko Koyama, Yasuyoshi Watanabe, Masaaki Suzuki
  • Journal Title: J. Label. Compd. Radiopharm. Volume: 57 Issue: 8 Pages: 540-549
  • DOI: 10.1002/jlcr.3213
  • Peer Reviewed
• [Journal Article] 11C-labeling of the C(1)-C(10) dihydroxy acid moiety for the study on the synthesis of kulokekahilide-2 PET tracer. (2014)
  • Author(s): Chunguang Han, Hisashi Doi, Junji Kimura, Yoichi Nakao, and Masaaki Suzuki
  • Journal Title: Int. J. Org. Chem. Volume: 4 Issue: 04 Pages: 269-277
  • DOI: 10.4236/ijoc.2014.44029
  • Peer Reviewed
• [Journal Article] Evaluation of breast cancer resistance protein function in hepatobiliary and renal excretion using PET with 11C-SC-62807. (2013)
  • Author(s): Takashima T, Wu C, Takashima-Hirano M, Katayama Y, Wada Y, Suzuki M, Kusuhara H, Sugiyama Y and Watanabe Y.
  • Journal Title: J Nucl Med Volume: 54 Issue: 2 Pages: 267-276
  • DOI: 10.2967/jnumed.112.110254
  • Peer Reviewed
• [Journal Article] Dynamic Analysis of Fluid Distribution in the Gastrointestinal Tract in Rats: Positron Emission Tomography Imaging after Oral Administration of Nonabsorbable Marker, [(18)F]Deoxyfluoropoly(ethylene glycol) (2013)
  • Author(s): Takashima T, Shingaki T, Katayama Y, Hayashinaka E, Wada Y, Kataoka M, Ozaki D, Doi H, Suzuki M, Ishida S, Hatanaka K, Sugiyama Y, Akai S, Oku N, Yamashita S, Watanabe Y
  • Journal Title: Mol. Pharmaceutics Volume: 10 Issue: 6 Pages: 2261-2269
  • DOI: 10.1021/mp300469m
  • Peer Reviewed
• [Journal Article] Pd0-Mediated Rapid Coupling of Methyl Iodide with Excess Amounts of Benzyl- and Cinnamylboronic Acid Esters: Efficient Method for Incorporation of Positron–Emitting 11C Radionuclide into Organic Frameworks by Coupling between Two sp3-Hybridized Carbons (2013)
  • Author(s): Hiroko Koyama, Zhouen Zhang, Ryosuke Ijuin, Siqin, Jeongwan Son, Yuma Hatta, Masashi Ohta, Masahiro Wakao, Takamitsu Hosoya, Hisashi Doi, Masaaki Suzuki
  • Journal Title: RSC Advances Volume: 3 Issue: 24 Pages: 9391-9401
  • DOI: 10.1039/c3ra40815a
  • Peer Reviewed
• [Journal Article] Synthesis of an 11C-Labeled Antiprion GN8 Derivative and Evaluation of Its Brain Uptake by Positron Emission Tomography (2013)
  • Author(s): Tsutomu Kimura, Takeo Sako, Siqin, Junji Hosokawa-Muto, Yi Long Cui, Yasuhiro Wada, Yosky Kataoka, Hisashi Doi, Suehiro Sakaguchi, Masaaki Suzuki, Yasuyoshi Watanabe, Kazuo Kuwata
  • Journal Title: ChemMedChem Volume: 8(7) Issue: 7 Pages: 1035-1039
  • DOI: 10.1002/cmdc.201300167
  • Peer Reviewed
• [Journal Article] Evaluation of Oatp and Mrp2 activities in hepatobiliary excretion using newly developed positron emission tomography tracer [11C]dehydropravastatin in rats. (2013)
  • Author(s): Shingaki T, Takashima T, Ijuin R, Zhang X, Onoue T, Katayama Y, Okauchi T, Hayashinaka E, Cui Y, Wada Y, Suzuki M, Maeda K, Kusuhara H, Sugiyama Y, Watanabe Y.
  • Journal Title: J Pharmacol Exp Ther Volume: 347 Issue: 1 Pages: 193-202
  • DOI: 10.1124/jpet.113.206425
  • Peer Reviewed
• [Journal Article] Evaluation of TlOH Effect for Pd0-Mediated Cross-Coupling of Methyl Iodide and Excess Boronic Acid Ester toward Fabrication of [11C]CH3-Incorporated PET Tracer. (2013)
  • Author(s): Hiroko Koyama, Hisashi Doi, Masaaki Suzuki
  • Journal Title: Int. J. Org. Chem. Volume: 3 Issue: 03 Pages: 220-223
  • DOI: 10.4236/ijoc.2013.33030
  • Peer Reviewed
• [Presentation] The Chemistry to Life Science: Highly Potentiated C-C Couplings (2016)
  • Author(s): Masaaki Suzuki
  • Organizer: King’s College London-Nagoya University Workshop in Cancer and Neuroscience
  • Place of Presentation: Nagoya University
  • Year and Date: 2016-03-10
  • Invited
• [Presentation] Evaluation of TlOH Effects for Pd0-Mediated Cross-Coupling of Methyl Iodide and Excess Boronic Acid Esters toward 11C-Incorporated PET Tracer Synthesis, Research area (10) Bench to Bedside (2015)
  • Author(s): Hiroko Koyama, Hisashi Doi, Masaaki Suzuki
  • Organizer: The International Chemical Congress of Pacific Basin Societies 2015
  • Place of Presentation: Honolulu, Hawaii, USA
  • Year and Date: 2015-12-15
  • Int'l Joint Research
• [Presentation] 11C-labeling of the C(1)-C(10) dihydroxy acid moiety for the study on the synthesis of kulokekahilide-2 PET tracer (2015)
  • Author(s): Chunguang Han, Hisashi Doi, Jyunji Kimura, Yoichi Nakao, Masaaki Suzuki
  • Organizer: The International Chemical Congress of Pacific Basin Societies 2015
  • Place of Presentation: Honolulu, Hawaii, USA
  • Year and Date: 2015-12-15
  • Int'l Joint Research
• [Presentation] Rh(I)-mediated rapid [11C]carboxylation using [11C]CO2 and organoborate at atmospheric pressure (2015)
  • Author(s): Miki Goto, Sachi Kurai, Ryo Yamamoto, Tomozumi Kanamitsu, Masaaki Suzuki, Yasuyohi Watanabe, Hisashi Doi
  • Organizer: The International Chemical Congress of Pacific Basin Societies 2015
  • Place of Presentation: Honolulu, Hawaii, USA
  • Year and Date: 2015-12-15
  • Int'l Joint Research
• [Presentation] 疾患対応新規PET分子プローブの革新的合成法と医学生物学的活用 (2015)
  • Author(s): 鈴木正昭
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-10-08
  • Invited
• [Presentation] A knack and pitfalls in the development of the novel 11C-labeled PET tracer synthesis (2014)
  • Author(s): Misato Takashima, Miho Shukuri, Mikako Ogawa, Yasuomi Ouchi, Hirotaka Onoe, Masaaki Suzuki, Yasuhiro Magata
  • Organizer: The 15th Conference of Peace through Mind/Brain Science
  • Place of Presentation: Hamamatsu
• [Presentation] 脳内aromataseとヒトの性格・気質との関連―PET 研究 (2014)
  • Author(s): 高橋佳代、細谷孝充、高島忠之、田中雅彰、石井聰、中富康仁、田沢周作、高橋和弘、土居久志、和田康弘、鈴木正昭、尾上浩隆、渡辺恭良
  • Organizer: 日本分子イメージング学会 第9回学会総会・学術集会
  • Place of Presentation: 千里ライフサイエンスセンター
• [Presentation] Imaging of cyclooxygenase-1 in activated microglia by PET with S-enantiomer of 11C-ketoprofen-methyl ester (2013)
  • Author(s): Miho Shukuri, Aya Mawatari, Masahiro Ohno, Hisashi Doi, Masaaki Suzuki, Yasuyoshi Watanabe, Hirotaka Onoe
  • Organizer: EANM'13-Annual Congress of the European Association of Nuclear Medicine
  • Place of Presentation: France・Lyon
• [Presentation] [11C]標識NSAIDsによるシクロオキシゲナーゼのPETイメージング (2013)
  • Author(s): 尾上浩隆、宿里充穂、鈴木正昭、渡辺恭良
  • Organizer: 第53回日本核医学会学術総会
  • Place of Presentation: 福岡・福岡国際会議場